ClinVar

In a female infant, born of unrelated Chinese Han parents, with progressive familial intrahepatic cholestasis-11 (PFIC11; 619874), Pan et al. (2021) identified a homozygous c.442C-T transition in exon 4 of the SEMA7A gene, resulting in an arg148-to-trp (R148W) substitution at a conserved residue in the SEMA domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Liver tissue from the patient was not available for analysis. Mutant mice homozygous for the orthologous mutation (R145W) developed elevated serum levels of liver enzymes ALT and AST and increased total bile acid associated with hydropic degeneration in hepatocytes. Liver tissue from mutant mice showed accumulation of bile acids and impaired hepatic excretion of bile acids compared to controls. There were also decreased protein levels of the canalicular bile acid transporters Bsep (ABCB11; 603201) and Mrp2 (ABCC2; 601107), although the mRNA levels of these genes were normal, suggesting post-translational regulation. These findings were consistent with cholestatic liver disease and recapitulated the human phenotype. Genetic analysis in the proband also identified a homozygous missense mutation in the SLC10A1 gene (S267F; 182396.0002) that may have contributed to the phenotype in the patient, although expression of the homozygous SLC10A1 mutation in mice did not lead to liver injury or hypercholanemia in mice, suggesting that the primary cause of the disease is the SEMA7A mutation.